Antihypertensive 1-substituted-4-(2-oxo-1-imidazolidinyl) piperidines

ABSTRACT

A process known per se for the manufacture of oxygenated N-aryl-diazacyclic compounds of the formula    &lt;IMAGE&gt;  (I)  wherein EACH OF R1 and R2 represents a substituted or unsubstituted aryl group and alk represents a lower alkylene group which separates both nitrogen atoms from each other by 2 or 3 carbon atoms, or salts thereof.

The invention relates to novel oxygenated N-aryl-diazacyclic compoundsof the formula ##STR2## wherein each of R₁ and R₂ represents asubstituted or unsubstituted aryl group and alk represents a loweralkylene group which separates both nitrogen atoms from each other by 2or 3 carbon atoms, and the salts thereof, as well as to a process fortheir manufacture and also to pharmaceutical preparations which containthese compounds and to their use, preferably in the form ofpharmaceutical preparations. An aryl group R₁ or R₂ is a carbocyclic orheterocyclic, preferably monocyclic and also bicyclic, aryl group.

A substituted or unsubstituted carbocyclic aryl group is preferably aphenyl group which can, for example, be mono-, di- or polysubstituted,and also a corresponding unsaturated or partially saturated naphthylgroup, such as 1- or 2-naphthyl, whilst a substituted or unsubstitutedheterocyclic aryl group is primarily a corresponding preferablymonocyclic and also bicyclic azaaryl group having 1 to 2 ring nitrogenatoms which can, for example, be mono-, di- or polysubstituted, such aspyridyl, for example 2-, 3- or 4-pyridyl, imidazolyl, for example2-imidazolyl, pyrimidinyl, for example 2- or 4-pyrimidinyl, pyridazinyl,for example 3-pyridazinyl, pyrazinyl, for example 2-pyrazinyl, indolyl,for example 4-indolyl, quinolyl, for example 4-quinolyl, or isoquinolyl,for example 1-isoquinolyl.

Substituents, chiefly of a carbocyclic aryl group, in particular of aphenyl group, include substituted or unsubstituted hydrocarbon radicals,such as substituted or unsubstituted lower alkyl, for example loweralkyl, optionally etherified or esterified hydroxy-lower alkyl, such ashydroxy-lower alkyl, lower alkoxy-lower alkyl or halogen-lower alkyl; orsubstituted or unsubstituted, for example acylated, amino-lower alkyl,such as lower alkanoyl-amino-lower alkyl or loweralkoxycarbonylamino-lower alkyl, or lower alkenyl or lower alkinyl,optionally etherified or esterified hydroxyl or mercapto, such ashydroxy, lower alkoxy which is unsubstituted or substituted for exampleby aryl, by optionally etherfied or esterified hydroxyl or mercapto orby acyl, for example lower alkoxy, phenyl-lower alkoxy, hydroxy-loweralkoxy, lower alkoxy-lower alkoxy, lower alkylthio-lower alkoxy,halogen-lower alkoxy or lower alkanoyl-lower alkoxy, or loweralkenyloxy, lower alkinyloxy, lower alkylthio or halogen, acyl, such asesterified carboxyl, for example lower alkanoyl or lower alkoxycarbonyl,amidated carboxyl, for example substituted or unsubstituted carbamoyl,cyano, nitro or substituted or unsubstituted, such as acylated, amino,for example lower alkanoylamino, lower alkoxycarbonylamino, substitutedor unsubstituted ureido, in addition N-lower alkylamino or N,N-di-loweralkylamino. Substituents of a heterocyclic aryl group are, for example,substituted or unsubstituted lower alkyl or optionally etherified oresterified hydroxyl or mercapto.

Lower alkylene represented by alk is preferably unbranched loweralkylene and primarily ethylene, and also 1,3-propylene, but can also bebranched lower alkylene, such as 1,2-propylene, 1,2- or 2,3-butylene.

The groups and compounds qualified by the term "lower" used hereinbeforecontain preferably not more than 7, and most preferably not more than 4,carbon atoms.

Lower alkyl is for example methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl or tert.-butyl. Substituted lower alkyl is in particularcorresponding methyl or 1- or 2-ethyl.

Lower alkenyl is for example vinyl, allyl, 2-, or 3-methalyl or3,3-dimethylallyl.

Lower alkinyl is in particular propargyl.

Lower alkoxy is for example methoxy, ethoxy, n-propyloxy, iso-propyloxy,n-butyloxy or iso-butyloxy.

Phenyl-lower alkoxy is for example benzyloxy or 1- or 2-phenylethoxy.

Lower alkenyloxy is for example allyloxy, 2- or 3-methallyloxy or3,3-dimethylallyloxy.

Lower alkinyloxy is in particular propargyloxy.

Lower alkylthio is for example methylthio, ethylthio, n-propylthio oriso-propylthio.

Halogen is preferably halogen with an atomic number not greater than 35,viz. fluorine, chlorine or bromine.

Lower alkanoyl is for example acetyl, propionyl or butyryl.

Lower alkoxycarbonyl is for example methoxycarbonyl or ethoxycarbonyl.

Substituted or unsubstituted carbamoyl if for example carbamoyl, orN-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, such asN-methyl-carbamoyl, N,N-dimethylcarbamoyl, N-ethylcarbamoyl orN,N-diethylcarbamoyl.

Lower alkanoylamino is for example acetylamino or propionylamino.

Lower alkoxycarbonylamino is for example methoxycarbonylamino orethoxycarbonylamino.

Substituted or unsubstituted ureido is for example ureido or 3-loweralkyl- or 3-cycloalkyl-ureido, wherein cycloalkyl contains for example 5to 7 ring members, for example 3-methylureido, 3-ethylureido or3-cyclohexylureido.

N-lower alkylamino and N,N-di-lower alkylamino are for examplemethylamino, ethylamino, dimethylamino or diethylamino.

Hydroxy-lower alkyl is preferably hydroxymethyl or 1-hydroxyethyl andchiefly 2-hydroxyethyl.

Lower alkoxy-lower alkyl is preferably lower alkoxymethyl or 1 -loweralkoxyethyl and chiefly 2-lower alkoxyethyl, for example methoxymethyl,ethoxymethyl, 2-methoxy-ethyl or 2-ethoxy-ethyl.

Halogen-lower alkyl is preferably halogen-methyl, for exampletrifluoromethyl.

Lower alkanoylamino-lower alkyl is in particular loweralkanoylamino-methyl or 1-lower alkanoylamino-ethyl and chiefly 2-loweralkanoylamino-ethyl, for example acetylamino-methyl, 2-acetylamino-ethylor 2-propionylamino-ethyl.

Lower alkoxycarbonylamino-lower alkyl is in particular loweralkoxycarbonylaminomethyl, or 1-lower alkoxycarbonylamino-ethyl andchiefly 2-alkoxycarbonylamino-ethyl, for examplemethoxycarbonylaminomethyl, 2-methoxycartionylamino-ethyl or2-ethoxycarbonylamino-ethyl.

Phenyl-lower alkoxy is in particular benzyloxy, but can also be 1- or2-phenylethoxy.

Lower alkoxy-lower alkoxy is, inter alia, lower alkoxymethoxy or 1-loweralkoxyethoxy and, in particular, 2-lower alkoxyethoxy, for examplemethoxymethoxy, 2-methoxyethoxy or 2-ethoxyethoxy.

Lower alkylthio-lower alkoxy is in particular lower alkylthiomethoxy or1-alkylthioethoxy and in particular 2-lower alkylthioethoxy, for example2-methylthioethoxy or 2 -ethylthioethoxy.

Halogen-lower alkoxy is in particular 2-halogenoethoxy, for example2-chloroethoxy.

Lower alkanoyl-lower alkoxy is for example lower alkanoylmethoxy or 1-or 2-lower alkanoylethoxy, for example acetylmethoxy.

The novel compounds can be in the form of their salts, for example theiracid addition salts and chiefly of their pharmaceutically acceptablenon-toxic acid addition salts. Examples of suitable salts are those withinorganic acids, such as hydrohalic acids, for example hydrochloric acidor hydrobromic acid; sulphuric acids, for example sulphuric acid; orphosphoric acids; or with organic acids, such as aliphatic,cycloaliphatic, aromatic or heterocyclic carboxylic or sulphonic acids,for example formics, acetic, propionic, succinic, glycolic, lactic,malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyruvic,fumaric, benzoic, 4-aminobenzoic, 4-aminobenzoic, anthranilic,4-hydroxybenzoic, salicylic, 4-aminosalicyclic, embonic,methanesulphonic, ethanesulphonic, 2-hydroxythanesulphonic,ethylenesulphonic, toluenesulphonic, naphthalenesulphonic or sulphanilicacid.

The novel compounds of the present invention can be in the form ofmixtures of isomers, such as racemates, or of pure isomers, for exampleoptically active antipodes.

The novel compounds possess valuable pharmacological properties. Forexample they possess a hypotensive action as can be demonstrated inanimal tests, for example in i.v. administration in doses of approx.0.03 to approx. 10 mg/kg to narcotised cats. In addition, the novelcompounds effect an antitachycardiac action, as can also be demonstratedin animal tests, for example in in vitro tests at concentrations ofapprox. 0.3 to approx. 10 ν/ml in guinea pig hearts (Langendorffpreparation), and an α-receptor blocking effect, for example in in vitrotests at concentrations of approx. 0.001 to approx. 0.1 ν/ml in rats[isolated perfused mesenteric arterial preparation; in a modification ofthe method of McGregor, J. Physiol., Vol. 177, p. 21 (1965)]. The novelcompounds can therefore be used as antihypertensives, antitachycardiacagents and α-receptor blockers. Furthermore, the novel compounds can beused as starting materials or intermediates for the preparation ofother, in particular therapeutically active, compounds.

The invention provides principally compounds of the formula I, whereineach of R₁ and R₂ represents a substituted or unsubstituted, mono- orbicyclic, carbocyclic aryl group or a substituted or unsubstitutedmonocyclic heteroaryl or benzoheteroaryl group having 1 or 2 ringnitrogen atoms, substituents of a carbocyclic aryl group being thoseselected from the group consisting of substituted or unsubstituted loweralkyl, for example lower alkyl, hydroxy-lower alkyl, lower alkoxy-loweralkyl, halogen-lower alkyl, lower alkanoylamino-lower alkyl, loweralkoxycarbonylamino-lower alkyl, or lower alkenyl, lower alkinyl,optionally etherified or esterified hydroxyl or mercapto, for examplehydroxyl, lower alkoxy, hydroxy-lower alkoxy, phenyl-lower alkoxy, loweralkoxy-lower alkoxy, lower alkylthio-lower alkoxy, halogen-lower alkoxy,lower alkanoyl-lower alkoxy, lower alkenyloxy, lower alkinyloxy, loweralkylthio, or halogen, acyl, for example lower alkanoyl, loweralkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl or N,N-di-loweralkylcarbamoyl, cyano, nitro and/or unsubstituted or substituted, suchas acylated, amino, for example amino, N-lower alkylamino, N,N-di-loweralkylamino, lower alkanoylamino, lower alkoxycarbonylamino, ureido,3-lower alkylureido or 3-cycloalkylureido, and substituents of aheterocyclic aryl or benzoaryl group being those selected from the groupconsisting of substituted or unsubstituted lower alkyl, for examplelower alkyl, or optionally etherified or esterified hydroxyl ormercapto, for example lower alkoxy, lower alkylthio, and/or halogen, andalk has the meaning given above, and salts, in particular acid additionsalts, primarily pharmaceutically acceptable, non-toxic acid additionsalts thereof.

The invention provides in particular compounds of the formula I, whereinR₁ represents phenyl or naphthyl which is unsubstituted or substitutedby a member selected from the group consisting of lower alkyl, forexample methyl, lower alkoxy-lower alkyl, such as 2-lower alkoxy-ethyl,for example 2-methoxyethyl, lower alkoxycarbonylamino-lower alkyl, suchas 2-lower alkoxycarbonylamino-ethyl, for example2-methoxycarbonylamino-ethyl, lower alkenyl, for example allyl,hydroxyl, lower alkoxy, for example methoxy, phenyl-lower alkoxy, forexample benzyloxy, lower alkoxy-lower alkoxy, such as 2-loweralkoxy-ethoxy, for example 2-methoxyethoxy, lower alkylthio-loweralkoxy, such as 2-lower alkylthio-ethoxy, for example2-methylthioethoxy, lower alkanoyl-lower alkoxy, such as loweralkanoylmethoxy, for example acetylmethoxy, lower alkenyloxy, forexample allyloxy, lower alkinyloxy, for example propargyloxy, loweralkylthio, for example methylthio, halogen, for example chlorine orbromine, lower alkanoyl, for example acetyl, lower alkoxycarbonyl, forexample methoxycarbonyl or ethoxycarbonyl, carbamoyl, N-lower alkyl- orN,N-di-lower alkylcarbamoyl, for example N-methylcarbamoyl orN,N-dimethylcarbamoyl, cyano, nitro, lower alkanoylamino, for exampleacetylamino, lower alkoxycarbonylamino, for examplemethoxycarbonylamino, 3-lower alkylureido, for example 3-methylureido,and/or 3-cycloalkylureido, for example 3-cyclohexylureido, or representsdiazaaryl having 6 ring members which is unsubstituted or substituted bya member selected from the group consisting of lower alkyl, for examplemethyl, lower alkoxy, for example methoxy, lower alkylthio, for examplemethylthio or ethylthio and/or halogen, for example pyrazinyl, R₂represents phenyl or naphthyl which is unsubstituted or substituted by amember selected from the group consisting of lower alkyl, for examplemethyl, halogen-lower alkyl, for example trifluoromethyl, lower alkoxy,for example methoxy, halogen, for example chlorine or bromine, loweralkanoyl, for example acetyl, lower alkoxycarbonyl, for examplemethoxycarbonyl or ethoxycarbonyl, carbamoyl, N-lower alkylorN,N-di-lower alkylcarbamoyl, for example N-methylcarbamoyl orN,N-di-methylcarbamoyl, nitro and/or N,N-di-lower alkylamino, forexample dimethylamino or diethylamino, or represents monocyclic orbicyclic mono- or diazaaryl which is unsubstituted or substituted by amember selected from the group consisting of lower alkyl, for examplemethyl, lower alkoxy, for example methoxy, and/or halogen, for examplechlorine or bromine, such as pyridyl, for example 2-, 3- or 4-pyridyl,quinolinyl or isoquinolinyl, for example 4-quinolinyl or1-isoquinolinyl, imidazolyl, for example pyrimidinyl, for example 2- or4-pyrimidinyl, pyridazinyl, for example 3-pyridazinyl, or pyrazinyl, forexample 2-pyrazinyl, and alk represents lower alkylene of 2 to 3 carbonatoms which separates both nitrogen atoms by 2 to 3 carbon atoms, forexample ethylene or 1,3-propylene, and salts, in particular acidaddition salts, chiefly pharmaceutically acceptable, non-toxic acidaddition salts thereof.

The invention provides more particularly compounds of the formula I,wherein R₁ represents phenyl which is unsubstituted or substituted by amember selected from the group consisting of lower alkyl, for examplemethyl, lower alkenyl, for example allyl, hydroxyl, lower alkoxy, forexample methoxy, phenyl-lower alkoxy, for example benzyloxy, loweralkanoyl-lower alkoxy, for example acetylmethoxy, lower alkenyloxy, forexample allyloxy, lower alkinyloxy, for example propargyloxy, halogen,for example chlorine or bromine, and/or cyano whilst one substituent canbe in any position, preferably however in the ortho-position, to thelinkage ring carbon atom of the phenyl radical, or represents2-pyrazinyl which is unsubstituted or substituted by a member selectedfrom the group consisting of lower alkyl, for example methyl, loweralkoxy, for example methoxy, lower alkylthio, for example methylthio orethylthio, and/or halogen, for example chlorine or bromine, whilst onesubstituent can be in any position, preferably however in theortho-position, to the linkage ring carbon atom of the pyrazinylradical, and R₂ represents phenyl or naphthyl which is unsubstituted orsubstituted by a member selected from the group consisting of loweralkyl, for example methyl, trifluoromethyl, lower alkoxy, for examplemethoxy, and/or halogen, for example chlorine or bromine, furthermore bylower alkanoyl, for example acetyl, lower alkoxycarbonyl, for examplemethoxycarbonyl or ethoxycarbonyl, carbamoyl, nitro and/or N,N-di-loweralkylamino, for example dimethylamino or diethylamino, or representspyridyl which is unsubstituted or substituted by a member selected fromthe group consisting of lower alkyl, for example methyl, lower alkoxy,for example methoxy, and/or halogen, for example chlorine or bromine,for example 2-, 3- or 4-pyridyl, and also represents correspondingpyrimidyl, for example 2- or 4-pyrimidinyl, pyridazinyl, for example3-pyridazinyl or 2-pyrazinyl, and alk represents lower alkylene of 2 to3 carbon atoms which separates both nitrogen atoms by 2 to 3 carbonatoms, for example ethylene or 1,3-propylene, and salts, in particularacid addition salts, primarily pharmaceutically acceptable, non-toxicacid addition salts thereof.

Particularly preferred compounds are those of the formula I wherein R₁represents phenyl which is substituted in the ortho-position by a memberselected from the group consisting of lower alkyl, for example methyl,lower alkenyl, for example allyl, lower alkoxy, for example methoxy,hydroxyl, benzyloxy, lower alkenyloxy, for example allyloxy, loweralkinyloxy, for example propargyloxy, lower alkanoyl-lower alkoxy, forexample acetylmethoxy, halogen, for example chlorine or bromine, orcyano, R₂ represents phenyl which is unsubstituted or substituted by amember selected from the group consisting of lower alkyl, for examplemethyl, trifloromethyl, lower alkoxy, for example methoxy, halogen, forexample chlorine or bromine, lower alkanoyl, for example acetyl, loweralkoxycarbonyl, for example methoxycarbonyl, carbamoyl, nitro and/ordi-lower alkylamino, for example dimethylamino, or represents pyridylwhich is unsubstituted or substituted by lower alkyl, for examplemethyl, or lower alkoxy, for example methoxy, for example 2- or4-pyridyl, and alk represents ethylene, and salts, in particular acidaddition salts, primarily pharmaceutically acceptable, non-toxic acidaddition salts thereof.

The most preferred compounds are those of the formula I wherein R₁represents phenyl which is substituted in the ortho-position by a memberselected from the group consisting of lower alkyl, for example methyl,lower alkenyl, for example allyl, lower alkenyloxy, for exampleallyloxy, halogen, for example chlorine or bromine, cyano or, inparticular, lower alkoxy, for example methoxy, R₂ represents phenylwhich is unsubstituted or substituted by a member selected from thegroup consisting of lower alkyl, for example methyl, lower alkoxy, forexample methoxy, or halogen, for example chlorine or bromine, orrepresents pyridyl, in particular 4-pyridyl, and alk representsethylene, and salts, in particular acid addition salts, primarilypharmaceutically acceptable, nontoxic acid addition salts thereof.

The novel compounds are obtained by methods which are known per se.Thus, for example, a compound of the formula

    R.sub.1 --O--X.sub.1                                        (II)

or a salt thereof, can be reacted with a compound of the formula##STR3## or with a salt thereof, wherein one of the radicals X₁ and X₂represents hydrogen and the other corresponds to the radical of theformula ##STR4## wherein X₃ represents a free hydroxyl group and X₄represents a reactive esterified hydroxyl group, or wherein X₃ and X₄together form an epoxy group, and, if desired, a resultant compound canbe converted into another compound of the formula I, and/or, if desired,a resultant free compound converted into a salt, and/or, if desired, aresultant salt converted into the free compound or into another salt,and/or, if desired, a resultant isomeric mixture separated into theindividual isomers.

The procedure which can be followed in carrying out the above reactioncomprises for example reacting a compound of the formula ##STR5## with acompound of the formula ##STR6## or reacting a compound of the formulaR₁ --OH (IIIb) with a compound of the formula ##STR7## wherein either X₃represents a free hydroxyl group and X₄ represents a reactive esterifiedhydroxyl group, or wherein X₃ and X₄ together represent an epoxy group.

A reactive esterified hydroxyl group X₄ is a hydroxyl group which isesterified by a strong inorganic or organic acid, preferably ahydrohalic acid, for example hydrochloric, hydrobromic or hydroiodicacid, also sulphuric acid, or by an organic sulphonic acid, such as anaromatic sulphonic acid, benzenesulphonic acid, 4-bromobenzenesulphonicacid or 4-toluenesulphonic acid. Provided it does not form an epoxygroup together with X₃, X₄ therefore represents in particular chlorineor bromine, and also iodine.

The above reaction is carried out in the customary manner. When using areactive ester as starting material of the formula (IIa), the process ispreferably carried out in the presence of a basic condensation agentand/or with an excess of the basic compound of the formula (IIIa).

If a reactive ester of the formula (IIb) is used as starting material,the compound of the formula (IIIb) is preferably used in the form of asalt, such as a metal salt, in particular an alkali metal salt, forexample a sodium or potassium salt, or the process is carried out in thepresence of an acid acceptor, in particular of a condensation agentwhich is able to form a salt with the compound of the formula (IIIb),such as an alkali metal lower alkanoate.

The above reaction is carried out in the absence, or preferably in thepresence, of a preferably inert solvent or diluent, and, if necessary,with cooling or heating, for example in a temperature range betweenapprox. 0° C and approx. 150° C, in a closed vessel and/or in an inertgas atmosphere, for example in an atmosphere of nitrogen.

The starting materials are known or they can be obtained in a mannerknown per se. For example, piperidine-4-one, wherein the secondary aminogroup can be protected in a manner known per se, for example by a benzylgroup or an easily removable acyl radical, can be reacted with a diamineof the formula H₂ N-alk-HN-R₂ (V) and simultaneously or subsequentlytreated with a suitable reducing agent, such as catalytically activatedhydrogen or with a hydride reducing agent, for example sodiumcyanoborohydride. The 2-oxo-1,3-diazacycloalkane radical is formed inthe intermediate thereby obtained by, for example, treatment with asuitable reactive derivative of carbonic acid, such as di-loweralkylcarbonate or phosgene. If necessary, a N-protective group can bereplaced in a manner known per se by hydrogen. A starting material ofthe formula (IIIa) thereby obtained can be converted into a startingmaterial of the formula (IIb) in a manner known per se, for example bytreatment with a reactive ester of 2,3-epoxy-1-propanol, such as a2,3-epoxy-1-propylhalide, and, if desired, by subsequent reaction with astrong acid, such as hydrohalic acid.

The novel compounds can also be obtained by converting X₅ into ahydroxyl group in a compound of the formula ##STR8## wherein X₅represents a group which can be converted into a hydroxyl group, and ifdesired, carrying out the additional process steps.

In a starting material of the formula (VI), X₅ is in particular anesterified hydroxyl group and chiefly an acyloxy group, wherein acylrepresents the corresponding radical of an organic carboxylic acid, suchas a lower alkanecarboxylic acid, for example an acetyl, propionyl orpivolyl, or of an aromatic carboxylic acid, for example benzoyl.

The conversion of X₅ into a hydroxyl group is effected by hydrolysis andthe process is carried out in an alkaline or acid medium. It is carriedout in the absence or presence of solvents or diluents, and, ifnecessary, with cooling or heating, for example in a temperature rangebetween approx. 0° C and approx. 120° C, in a closed vessel and/or in aninert gas atmosphere.

The starting materials of the formula (VI) can be obtained for exampleby converting X₃ into an acyloxy group in a compound of the formula(IIa), wherein X₃ represents a hydroxyl group and X₄ represents areactive esterified hydroxyl group, for example by acylation with areactive derivative such as an optionally mixed anhydride or an organiccarboxylic acid, and the intermediate thereby obtained, preferably anexcess thereof, is reacted with a compound of the formula (IIIa).

The novel compounds can also be obtained by reducing the pyridinium ringin a compound of the formula ##STR9## wherein X⊖ represents an anion, togive the piperidine ring, and, if desired, carrying out the additionalprocess steps.

An anion X⊖ is in particular that of an acid, preferably of a mineralacid, such as a hydrohalic acid, for example hydrochloric or hydrobromicacid, or of a suitable organic carboxylic or sulphonic acid.

The above reaction can be carried out in conventional manner, preferablyby means of catalytic hydrogenation, such as with hydrogen in thepresence of a suitable hydrogenation catalyst, for example a heavy metalcatalyst, for example a palladium, platinum or Raney nickel catalyst, orby treatment with nascent hydrogen, such as by treatment with an alkalimetal, for example sodium or potassium, in the presence of an alcohol,such as a lower alkanol, for example ethanol or n-butanol.

Moreover, the reaction, in which care must be taken that other reduciblegroups remain intact, can also take place stepwise, since partiallysaturated pyridine compounds, for example 1,2,5,6-tetrahydropyridinecompounds, can be formed as intermediates, which can be converted intothe desired piperidine compounds by treatment with the same reducingagent, optionally under different conditions, or with another reducingagent.

The above reaction is carried out in the absence, and in particular inthe presence, of a solvent or diluent, and if necessary, with cooling orheating, for example in a temperature range between approx. 0° C andapprox. 120° C, in a closed vessel and/or in an inert gas atmosphere.

The starting materials can be prepared in a manner known per se by, forexample, reacting 4-amino-pyridine with a compound of the formula

    Hal.sub.1 -alk.sub.o -C(═O)-NH-R.sub.2                  (VIII)

(which is obtained for example by treating an amino compound of theformula H₂ N-R₂ (IX) with an acid halide of the formula Hal₁ -alk_(o)-C(═O)-Hal₂ (X), wherein each of Hal₁ and Hal₂ represents a halogenatom, for example a chlorine atom) and alk_(o) corresponds to the loweralkylene group alk which contains one carbon atom less in the chain. Thecarbonyl group in the intermediate thereby obtained of the formula##STR10## is reduced to the methylene group, for example by treatmentwith lithium aluminium hydride, and the 2-oxo-1,3-diazacycloalkane ringis formed, for example by treatment with phosgene. The resultant4-(2-oxo-3-R₂ -1,3-diazacycloalk-1-yl)-pyridine compound is then reactedwith a compound of the formula IIa, wherein X₃ represents a hydroxylgroup and X₄ represents a reactive esterified hydroxyl group, and inparticular halogen.

The novel compounds of the formula I can also be obtained by forming the2-oxo-1,3-diazacycloalkane ring in a compound of the formula ##STR11##wherein one of the radicals X₆ and X₇ represents a hydrogen atom and theother represents the acyl radical of a hemiderivative of carbonic acid,cyclisation, and, if desired, carrying out the additional process steps.

In a starting material of the formula (XII), the acyl radical of ahemiderivative of carbonic acid represents the corresponding radical ofa carbonic acid hemiester, such as lower alkoxycarbonyl, for examplemethoxycarbonyl or ethyoxycarbonyl, of a carbonic acid hemihalide, forexample chlorocarbonyl or bromocarbonyl, or of a carbonic acidhemiamide, for example carbamoyl.

The cyclisation is carried out in the absence or presence of a solventor diluent, and, if necessary, in the presence of a preferably basiccondensation agent, for example a hydroxide, carbonate, hydrogencarbonate or lower alkanoate of an alkali metal or alkaline earth metal,and of an organic base of the pyridine type, with cooling or preferablyheating, for example in a temperature range between approx. 20° toapprox. 150° C, in a closed vessel and/or in an inert gas atmosphere.

The starting material of the formula (XII) is prepared by methods knownper se, and preferably in situ by reacting a compound of the formulaXII, wherein each of X₆ and X₇ represents a hydrogen atom, with areactive derivative of carbonic acid. Reactive derivatives of carbonicacid are corresponding esters, such as a di-lower alkylcarbonate, forexample diethyl carbonate, or halides, for example phosgene, furthermoreamides, for example urea or carbonyldiimidazole, and also halogenatedcarbonic acid esters, for example isobutyl chlorocarbonate, or halides,for example the chloride, of carbamic acid.

The reaction is carried out in conventional manner, ordinarily in thepresence of an inert solvent, preferably an optionally halogenatedaliphatic or aromatic hydrocarbon, for example chloroform or toluene,furthermore of an amide or nitrile, for example dimethyl formamide,dimethyl acetamide or acetonitrile, or of a cycloaliphatic ether, suchas dioxane and tetrahydrofurane. The reaction is preferably carried outin the presence of a condensation agent, in particular of a basic agent,such as hydroxide, carbonate or hydrogen carbonate of an alkali metal oralkaline earth metal, for example sodium or potassium hydroxide, sodiumor potassium carbonate or sodium or potassium hydrogen carbonate, or ofan alkali metal lower alkanoylate, for example sodium acetate, or of analkali metal lower alcoholate, for example sodium methanolate orpotassium tert. -butanolate, or of an organic tertiary nitrogen base,such as a tri-lower alkylamine, for example trimethylamine ortriethylamine, or pyridine.

A compound of the formula (XII), wherein each of X₆ and X₇ represents ahydrogen atom, can be obtained for example by reacting piperidine-4-onewith a compound of the formula (IIa), wherein X₃ represents a hydroxylgroup and X₄ represents a reactive esterified hydroxyl group, inparticular halogen, and subsequently reacting the intermediate therebyobtained with a diamine of the formula (V), with simultaneous orsubsequent treatment with a reducing agent, such as catalyticallyactivated hydrogen or with a suitable hydride reducing agent, forexample cyanoborohydride.

The novel compounds of the formula I can also be obtained by convertingX₈ into the oxo group in a compound of the formula ##STR12## wherein X₈represents a radical which can be converted into the oxo group, and, ifdesired, carrying out the additional process steps.

The radical X₈ is for example imino. A corresponding starting materialof the formula (XIII) can be converted into the corresponding compoundof the formula I by hydrolysis, preferably in the presence of an acidagent, such as a mineral acid, for example hydrochloric acid.

The above reaction is carried out in the absence, or preferably in thepresence of a solvent or diluent, and, if necessary, with cooling orheating, for example in a temperature range between approx. 0° toapprox. 150° C, in a closed vessel and/or in an inert gas atmosphere.

The starting materials of the formula (XIII) can be obtained in a mannerknown per se, for example by treating a compound of the formula (XII),wherein each of the radicals X₆ and X₇ represents a hydrogen atom, witha halocyanogen, for example bromocyanogen, preferably in the presence ofa suitable, for example basic, condensation agent, with simultaneous orsubsequent cyclisation to give the 2-imino1,3-diazacycloalkene ring ofthe starting material of the formula (XIII).

Within the scope of the end products, substituents in resultantcompounds can be split off, introduced or converted in a manner knownper se.

Thus in compounds of the formula I with unsaturated substituents, forexample lower alkenyl, lower alkenyloxy or lower alkinyloxy, it ispossible to reduce these substituents by suitable reduction methods togive saturated compounds, or to reduce substituents with a triple bondto give compounds with a double bond. Catalytically activated hydrogenis preferably used as reducing agent, whilst a chemical reducing agent,such as sodium in the presence of liquid ammonia, is also used for thereduction of a triple bond.

In a compound of the formula I, which contains a halogen atom, such as abromine or iodine atom, as substituent of an aromatic radical, it isalso possible to replace the halogen atom by a trifluoromethyl group by,for example, treatment with trifluoromethyl iodide in the presence ofcopper powder and a suitable aprotic solvent, such as pyridine, dimethylformamide or acetonitrile.

In a compound of the formula I, an α-phenyl-lower alkyl group, forexample in a benzyloxy group, can be split off by treating thecorresponding compound with catalytically activated hydrogen, and, forexample, a benzyloxy group can be replaced by hydroxy by means ofhydrogen.

Furthermore, in a compound of the formula I, which contains hydroxyl ormercapto in the form of a primary carbinol or a phenolic hydroxyl groupas substituent, said substituent can be converted into an etherifiedhydroxyl or mercapto group by treating the compound, optionally in theform of a salt, for example an alkali metal salt, with a reactive esterof an alcohol, such as an optionally substituted lower alkyl halide. Inaddition, a hydroxyl group in a hydroxy-lower alkyl or hydroxy-loweralkoxy substituent, usually in the form of a reactive esterifiedhydroxyl group, can be reacted with an alcohol, for example a loweralkanol, or with a mercaptan, for example a lower alkylmercaptan,preferably in the presence of a base which is capable of converting forexample an alcohol or a mercaptan into a metal compound, and in this wayit is possible to obtain compounds of the formula I, which containhydroxyl or etherified hydroxylor mercapto-lower alkyl or mercapto-loweralkoxy groups.

In a compound of the formula I it is possible to convert a propargyloxygroup into the acetonyloxy group, for example by hydration in acidmedium and in the presence of a mercury(II) salt, for example bytreatment with an aqueous mineral acid, for example dilute hydrochloricor sulphuric acid, in the presence of mercury(II) chloride.

Furthermore, in a compound of the formula I, which contains assubstituent esterified carboxyl or lower alkoxycarbonylamino, whissubstituent can be converted by treatment with ammonia or an amine,preferably with an excess thereof and at elevated temperature, intoamidated carboxyl or optionally substituted ureido.

It is also possible in a compound of the formula I, which contains assubstituent a primary amino group, to substitute this group. Thus theamino group can be acylated, for example by treating the amino compoundwith a suitable acid derivative, such as an optionally mixed anhydride,for example a corresponding chloride, if necessary in the presence of abase.

The above described reactions can, if appropriate, be carried outsimultaneously or in succession and in any desired sequence andconventional manner, for example in the presence or absence of solventsor diluents, if necessary in the presence of condensation and/orcatalytic agents, with cooling or heating, in a closed vessel and/or inan inert gas atmosphere.

Depending on the process conditions and the starting material, the endproducts are obtained in the free form or in the form of their salts, inparticular their acid addition salts, which are also comprised by thepresent invention. Resultant salts can be converted in known manner intothe free compounds, acid addition salts for example by treatment withbases, including suitable ion exchangers. On the other hand, resultantfree compounds can form salts, for example by treatment with organic orinorganic acids, In addition, resultant salts, viz. acid addition salts,can be converted into other salts, for example by treatment withsuitable heavy metal salts or anion exchangers.

The above mentioned salts or other salts of the novel compounds of theformula I, for example the picrates, can also be used for purifying theresultant free bases by converting the free bases into salt, separatingthese and once more liberating the bases from the salts. Because of theclose relationship between the novel compounds in the free form and inthe form of their salts, what is stated in this specification in respectof the free compounds refers also to the corresponding salts, whereverthis applies.

Depending on the choice of the starting materials and process methods,the novel compounds are obtained in the form of the racemates or opticalantipodes.

Racemates can be separated by means of known methods into the opticalantipodes, for example by recrystallisation from an optically activesolvent, with the aid of microorganisms or by reaction with an opticallyactive acid which forms salts with the racemic compound and separationof the salts obtained in this way, for example on the basis of theirdifferent solubilities, into the diastereomeric salts from which thefree antipodes can be liberated by treatment with suitable agents.Particularly suitable optically active acids are for example, the D- andL-forms of tartaric acid, di-toluyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid or guinic acid.

The invention also relates to those modifications of the process inwhich a compound obtainable in any stage as intermediate is used asstarting material and the missing process steps are carried out, or theprocess is discontinued at any stage, or in which a starting material isformed under the reaction conditions or in which a reaction component isoptionally in the form of a derivative for example in the form of asalt.

It is advantageous to use for carrying out the reactions of the presentinvention those starting materials which result in the groups of endproducts particularly referred to at the outset and especially in theend products described or singled out for special mention.

The novel compounds can be used for example in the form ofpharmaceutical preparations which contain an effective amount of theactive substance, if appropriate together with inorganic or organic,solid or liquid pharmaceutically useful carriers suitable for enteral,for example oral, or parenteral administration. Tablets or gelatincapsules are therefore used which contain the active substance togetherwith diluents, for example lactose, dextrose, sucrose, mannitol,sorbitol, cellulose and/or glycin, and lubricants, for example silica,talc, stearic acid or salts thereof, such as magnesium or calciumstearate, and/or polyethylene glycol. Tablets also contain bindingagents, for example magnesium aluminium silicate, starches, such asmaize, corn, rice or arrow root starch, gelatins, tragacanth, methylcellulose, sodium carboxymethyl cellulose and/or polyvinyl pyrrolydine,and, if desired, disintegrators, for example starches, agar, alginicacid or a salt thereof, such as sodium alginate, and/or effervescentmixtures, or adsorption agents, dyes, flavouring matters and sweetners.It is also possible to use the novel pharmacologically active compoundsin the form of preparations for parenteral administration or of infusionsolutions. Such solutions are preferably isotonic aqueous solutions orsuspensions which can be manufactured before use, for example fromlyophilised preparations that contain the active substance alone ortogether with a carrier, for example mannitol. The pharmaceuticalpreparations can be sterilised and/or contain adjuvants, for examplepreservatives, stabilisers, wetting agents and/or emulsifiers,solubility promoters, salts for regulating the osmotic pressure and/orbuffers. The pharmaceutical preparations which, if desired, can containfurther pharmacologically useful substances, are manufactured in knownmanner, for example using conventional mixing, granulating,confectioning, dissolving or lyophilising methods, and they contain fromabout 0.1 % to 100 %, especially from about 1 % to about 50 %, oflyophilisates up to 100 % of the active substance. The dosage can dependon a variety of factors, such as mode of application, species, ageand/or individual condition. The daily doses for oral administration arebetween about 1 mg and about 15 mg for warm-blooded animals having aweight of approx. 70 kg.

The invention is illustrated by the followng Examples.

EXAMPLE 1

With vigorous stirring, a solution of 117 ml of a 20% phosgene solutionin toluene is added dropwise at a reaction temperature of 5° to 10° C toan emulsion of 10 g of1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-(2-anilino-ethylamino)-piperidinein 60 ml of toluene and 37.5 ml of a 3N aqueous sodium hydroxidesolution over 11/4 hours. Thereafter 35.5 ml of a 6N aqueous potassiumhydroxide solution are added dropwise at the same reaction temperaturein the course of half an hour. Stirring is continued for 30 minutes at5° to 10° C and for 20 hours at room temperature. The reaction mixtureis filtered with suction and the crystalline residue is treated withtoluene. Recrystallisation from isopropanol yields1-{1-[2-hydroxy-3-(2-methoxy-phenyloxy)-propyl]-4-piperidyl}-3-phenyl-imidazolidin-2-one-hydrochloridein the form of white crystals with a melting point of 185°- 187° C. Thesalt can be converted into the free compound for example by treatmentwith an aqueous sodium hydroxide solution.

The starting material can be prepared as follows:

A mixture of 20 g of the hydrate of 4-piperidone-hydrochloride, 46.8 gof 1-(2-methoxyphenyloxy)-2,3-epoxy-propane, 18 g of potassium carbonateand 250 ml of isopropanol is stirred for 6 hours at a reactiontemperature of 60° C. After cooling, the suspension is filtered and thefiltrate is evaporated to dryness under reduced pressure. The residue isdissolved in 100 ml of 6N hydrochloric acid and washed with four 75 mlportions of ethyl acetate. The aqueous acid solution is adjusted with a2N sodium carbonate solution to a pH of 10 and extracted with three 75ml portions of ethyl acetate. The organic extracts are dried over sodiumsulphate and concentrated under reduced pressure. The red residue isdissolved in methanol and the solution is boiled for 30 minutes with theaddition of activated charcoal. The solution is filtered and thefiltrate is concentrated under reduced pressure. The residue is treatedwith toluene and recrystallised from a mixture of ethyl acetate andpetroleum ether to give1-[2-hydroxy-(2-methoxyphenyloxy)-propyl]-piperidin-4-one with a meltingpoint of 77°-78° C.

A solution of 16.7 g of1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-piperidine-4-one and 10.5 gof N-(2-aminoethyl)-aniline in 250 ml of methanol, with the addition of1 g of a 5% platinum on charcoal catalyst is hydrogenated at roomtemperature and under normal pressure until 1 molar equivalent ofhydrogen has been taken up. The catalyst is thereafter removed byfiltration and the filtrate is concentrated under reduced pressure. Theresidue is freed from excess starting material in a bulb tube at 0.3 mmHg and 120° C oven temperature to yield as distillation residue1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-(2-anilino-ethylamino)-piperidine,which can be used without further purification.

EXAMPLE 2

With stirring, 392 ml of an approx. 20% solution of phosgene in tolueneare added dropwise at a reaction temperature of 5° to 10° C in thecourse of 1 hour to a mixture of 31.5 g of1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-[2-(4-pyridylamino)-ethylamino]-piperidinein 300 ml of toluene and 126 ml of 3N aqueous potassium hydroxidesolution. Thereafter 120 ml of a 6N aqueous potassium hydroxide solutionare added dropwise at the same temperature in the course of 30 minutes.The reaction mixture is further stirred for 30 minutes at 10° C and for20 hours at room temperature. The aqueous acid phase is separated,concentrated to a volume of approx. 50 ml and made alkaline with aconcentrated aqueous solution of ammonia. The emulsion is extracted withfour 75 ml portions of methylene chloride. The combined methylenechloride phases are dried over sodium sulphate and concentrated. Theresidue is chromatographed through a column of 800 g of silica gel usinga 9:1 mixture of methylene chloride and methanol as eluant. The purified1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-(4-pyridyl)-imidazolidin-2-oneis taken up in methanol and the solution is acidified with methanolichydrochloric acid. The acid solution is concentrated under reducedpressure. The residue is treated with toluene and recrystallised from amixture of methanol and diethyl ether to yield the1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-(4-pyridyl)-imidazolidin-2-one-dihydrochloridein the form of the hemihydrate; m.p. 230°-234° C.

The starting material can be prepared as follows:

A mixture of 38.9 g of 4-bromo-pyridine-hydrochloride and 480 g ofethylenediamine is refluxed with stirring for 13 hours. The reactionmixture is thereafter concentrated under reduced pressure and theresidue is treated with toluene and concentrated once more. The residueis made alkaline with a concentrated aqueous solution of sodiumhydroxide and extracted with five 75 ml portions of methylene chloride.The combined extracts are dried over sodium sulphate and concentratedunder reduced pressure. Recrystallisation of the residue from methylenechloride yields 4-(2-aminoethylamino)-pyridine as a light yellowcrystalline substance with a melting point of 120°-121° C.

A solution of 27.9 g of1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-piperidin-4-one and 22.8 gof 4-(2-aminoethylamino)-piperidine in 250 ml of methanol, with theaddition of 2 g of a platinum on charcoal catalyst, is hydrogenated atroom temperature and under normal pressure until 1 molar equivalent hasbeen taken up. The catalyst is thereafter removed by filtration and thefiltrate is concentrated under reduced pressure. The residue isdissolved in 500 ml of methylene chloride and the solution is washedwith three 150 ml portions of water, dried over sodium sulphate andconcentrated under reduced pressure to yield1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-[2-(4-pyridyl-amino)-ethylamino]-piperidine,which can be processed without further purification.

EXAMPLE 3

With vigorous stirring, 630 ml of a 20% solution of phosgene in tolueneare added dropwise at a reaction temperature of 5° to 10° C in thecourse of 13/4 hours to an emulsion of 56 g of1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-[2-(4-chloroanilino)-ethylamino]-piperidinein 340 ml of toluene and 200 ml of a 3N potassium hydroxide solution.Thereafter 193 ml of a 6N aqueous potassium hydroxide solution are addeddropwise at the same reaction temperature in the course of half an hour.The reaction mixture is further stirred for 1 hour at 5° to 10° C andfor 20 hours at room temperature and then concentrated. The residue ismade alkaline with a 2N aqueous sodium hydroxide solution and extractedwith five 100 ml portions of methylene chloride. The extracts are driedover sodium sulphate and concentrated under reduced pressure. Theresidue is dissolved in methanol and boiled for 30 minutes with theaddition of activated charcoal. The batch is filtered and the filtrateis concentrated under reduced pressure. The residue is treated withtoluene and recrystallised from isopropanol to yield1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-(4-chlorophenyl)-imidazolidin-2-onewith a melting point of 136°-137° C.

The1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-[2-(4-chloroanilino)-ethylamino]-piperidinecan be prepared as follows:

A mixture of 38 g of p-chloroaniline and 31 g of2-bromoethylamine-hydrobromide is heated to 70° C with stirring. After30 minutes 75 ml of diethyl ketone are added and the mixture is refluxedfor 4 hours. The black solution is then concentrated under reducedpressure. The residue is made alkaline with 2N sodium carbonate solutionand extracted with three 100 ml portions of chloroform. The residual oilis fractionally distilled in vacuo to yield1-(4-chlorophenyl)-ethylenediamine with a boiling point of 130°-135° C(1.5 torr).

A solution of 33.5 g of1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-piperidin-4-one and 20.5 gof 1-(4-chlorophenyl)-ethylenediamine in 300 ml of methanol, with theaddition of 1.5 g of a 5% platinum on charcoal catalyst, is hydrogenatedat room temperature and under normal pressure until 1 molar equivalentof hydrogen has been taken up. The catalyst is then removed byfiltration and the filtrate is concentrated under reduced pressure. Theresidue is treated with toluene to give the1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-[2-(4-chloroanilino)-amino]-piperidineas a reddish oil which can be used without further purification.

EXAMPLE 4

A mixture of 17.9 g of1-[4-methoxy-phenyl)-3-(4-piperidyl)-2-imidazolidinone and 11.7 g of1-(2-methoxyphenyloxy)-2,3-epoxypropane in 200 ml of isopropyl alcoholis refluxed for 6 hours. The mixture is thereafter acidified with 5Nmethanolic hydrochloric acid and concentrated under reduced pressure.The residue is freed from moisture still adhering to it by treatmentwith toluene. Recrystallisation of the residue from methanol with theaddition of activated charcoal yields the1-{1-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-4-piperidyl}-3-(4-methoxy-phenyl)-imidazolidin-2-one-hydrochlorideas a white crystalline substance with a melting point of 214°-215° C.

The 1-(4-methoxy-phenyl)-3-(4-piperidyl)-2-imidazolidinone used asstarting material can be prepared as follows:

A mixture of 61.5 g of 4-methoxy-aniline and 51.3g of2-bromoethylamine-hydrobromide in 125 ml of methyl ethyl ketone isrefluxed for 5 hours with stirring. The viscous suspension is thereafterevaporated to dryness under reduced pressure. The residue is suspendedin 150 ml of isopropanol and then collected by filtration. The filtercake is washed with three 50 ml portions of isopropanol and with two 50ml portions of diethyl ether. The crystalline product is made alkalinewith a concentrated aqueous ammonia solution and extracted with five 50ml portions of chloroform. The extracts are dried over sodium sulphateand concentrated under reduced pressure. The oily residue crystallisesafter trituration to give the 1-(4-methoxyphenyl)-ethylenediamine with amelting point of 64° C.

A solution of 33 g of 1-benzyl-4-piperidone and 29 g of1-(4-methoxy-phenyl)-ethylenediamine in 310 ml of methanol, with theaddition of 1 g of a 5% platinum on charcoal catalyst, is hydrogenatedat room temperature and under normal pressure until 1 molar equivalentof hydrogen has been taken up. The catalyst is thereafter removed byfiltration and the filtrate concentrated. The residue is treated withtoluene to yield the1-benzyl-4-[2-4-methoxy-anilino)-ethylamino]-piperidine as a yellowishoil, which is used without purification.

With vigorous stirring, 87 g of phosgene gas are introduced at 5° to 10°C in the course of 21/2 hours into a mixture of 63 g of1-benzyl-4-[2-4-methoxy-anilino)-ethylamino]-piperidin in 570 ml oftoluene and 285 ml of 2 3N aqueous potassium hydroxide solution.Stirring is continued for a further 2 hours at room temperature and then252 ml of a 6N aqueous potassium hydroxide solution are added dropwisein the course of 15 minutes, when a slightly exothermic reaction occurs.The reaction mixture is stirred for a further 20 hours at roomtemperature. Thereafter the organic phase is separated and the alkalineaqueous phase is extracted with two 100 ml portions of toluene. Theorganic extracts are dried over sodium sulphate and concentrated underreduced pressure. The residue is treated with toluene and recrystallisedfrom isopropanol to yield1-(1-benzyl-4-piperidyl)-3-(4-methoxy-phenyl)-imidazolidin-2-one with amelting point of 144°-147° C.

A mixture of 44 g of1-(1-benzyl-4-piperidyl)-3-(4-methoxy-phenyl)-imidazolidin-2-one, 320 mlof methanol, 130 ml of water and 12 g of a conc. aqueous solution ofhydrochloric acid, with the addition of 10 g of a palladium on charcoalcatalyst, is hydrogenated at 30° to 40° C and under reduced pressureuntil 1 molar equivalent of hydrogen has been taken up. Thereafter thecatalyst is removed by filtration and the filtrate is concentrated underreduced pressure. The residue is treated with toluene and recrystallisedfrom a mixture of isopropyl alcohol and diethyl ether to yield the1-(4-methoxyphenyl)3-(4-piperidyl)-2-imidazolidinone with a meltingpoint of 140° C.

EXAMPLE 5

A mixture of 7.1 g of 2-methyl-4-(2,3-epoxy-propyl)-indole and 9.6 g of1-(4-methoxy-phenyl)-3-(4-piperidyl)-2-imidazolidinone is dissolved in125 ml of isopropyl alcohol and the solution is refluxed for 6 hours.Thereafter the reaction solution is cooled on an ice bath and theprecipitate which has formed is collected by filtration. The crystallineprecipitate is dissolved in methyl alcohol and the solution is stronglyacidified with 5N methanolic hydrochloric acid. The acid solution isconcentrated and the crystalline residue is freed from moisture adheringto it by treatment with toluene. Recrystallisation from methanol-etheryields the1-{1-[2-hydroxy-3-(2-methyl-1H-indol-4-yloxy)-propyl]-4-piperidyl}-3-(4-methoxyphenyl)-imidazolidin-2-onewith a melting point of 155°-157° C.

EXAMPLE 6

7.27 g of 2-chloro-3-(2,3-epoxy-propoxy)-pyrazine and 7.35 g of1-(4-piperidyl)-3-phenyl-2-imidazolidinone in 120 ml of isopropanol arestirred for 24 hours at approx. 20° C. The reaction mixture is thenconcentrated in a water jet vacuum. The residue crystallises from etherand yields1-{1-[2-hydroxy-3-(3-chloro-pyrazin-2-yloxy)-propyl]-4-piperidinyl}-3-phenyl-imidazolidin-2-onewith a melting point of 122°-124° C.

The starting material can be prepared as follows:

9.8 g of N-phenylethylenediamine and 13.9 g of 1-benzyl-4-piperidone aredissolved in 200 ml of methanol and, with the addition of 0.7 g of a 5%platinum on charcoal catalyst, hydrogenated at room temperature andunder normal pressure. The calculated amount of hydrogen is taken upafter approx. 3 hours. The reaction mixture is filtered to remove thecatalyst and concentrated in a water jet vacuum. The residue crystalisesfrom methanol/water to yield 21.4 g of1-benzyl-4-(2-phenylamino-ethylamino)-piperidino with a melting point of78°-81° C.

With stirring, 15 g of phosgene are introduced at 5° to 10° C in thecourse of 1 hour into a suspension of 10 g of1-benzyl-4-(2-phenylamino-1-ethylamino)-piperidine in 100 ml of tolueneand 48.5 ml of 3N potassium hydroxide solution. After stirring for 2hours at 5° to 10° C, the reaction mixture is made alkaline with 43 mlof 6N potassium hydroxide solution and brought to room temperature.After it has been stirred for a further 15 hours at room temperature,the reaction mixture is filtered with suction and the residue isrecrystallised from isopropanol-methanol to yield 7.2 g of1-(1-benzyl-4-piperidinyl)-3-phenyl-2-imidazolidinone.

11.1 g of 1-(1-benzyl-4-piperidinyl)-3-phenyl-2-imidazolidinone aredissolved in 85 ml of methanol, 34 ml of water and 3.2 ml ofhydrochloric acid (chemically pure), and, with the addition of 1.2 g ofa 5% palladium on charcoal catalyst, hydrogenated at room temperatureand under normal pressure. The calculated amount of hydrogen has beentaken up after approx. 15 hours. The reaction mixture is filtered toremove the catalyst and concentrated in a water jet vacuum. Thecrystalline residue is treated with 2N sodium carbonate solution andextracted with chloroform. The combined chloroform extracts are driedover sodium sulphate and concentrated in a water jet vacuum to yield 7.6g of 1-(4-piperidinyl)-3-phenyl-2-imidazolidinone as a colourless oilwhich crystallises on standing; melting point 123°-124° C.

EXAMPLE 7

With stirring, 10.1 g of1-{1-[2-hydroxy-3-(3-chloropyrazin-2-yloxy)-propyl]-4-piperidinyl}-3-phenyl-imidazolidin-2-one(see Example 6) and 1.41 g of sodium methylate in 110 ml of methanol arerefluxed for 10 hours. The reaction mixture is concentrated in a waterjet vacuum. The residue is dissolved in ethyl acetate and extracted with2N hydrochloric acid. The combined hydrochloric acid extracts are madealkaline with conc. ammonia and extracted with methylene chloride. Thecombined methylene chloride extracts are washed with water, dried oversodium sulphate and concentrated in a water jet vacuum. The residuecrystallises from methylene chloride-ether to yield1-{1-[2-hydroxy-3-(3-methoxy-pyrazin-2-yloxy)-propyl]-4-piperidinyl}-3-phenyl-imidazolidin-2-one with a melting point of 128°-129° C.

The hydrochloride, which is prepared with methanolic hydrochloric acids,crystallises from methanol-acetone; melting point 209°-210° C.

EXAMPLE 8

5 g of1-{1-[2-acetoxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-phenyl-imidazolid-1-onein a 2N solution of potassium hydroxide in alcohol are allowed to standfor 12 hours at room temperature. The mixture is thereafter evaporatedto dryness and the residue is dissolved in water and extracted withethyl acetate. The organic solution is dried and concentrated. Afteraddition of methanolic hydrochloric acid, the1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-phenylimidazolidin-2one-hydrochloride crystallises out.After recrystallisation from isopropanol, it melts at 185°-187° C.

EXAMPLE 9

At room temperature, 5 g of1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-pyridinium}-3-phenyl-imidazolidin-2-one-bromide are reduced with 500mg of sodium borohydride in 55 ml of an alcohol-water mixture (1:1) for3 hours. The reaction mixture is filtered and the filtrate is evaporatedto dryness. The residue is recrystallised from ethyl acetate-petroleumether to yield 1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-(1,2,5,6-tetrahydro-pyridyl}-3-phenyl-imidazolidin-2-one, which isdissolved in alcohol and hydrogenated with platinum oxide as catalyst.After the calculated amount of hydrogen has been taken up, the catalystis filtered off and the solution is evaporated to dryness. Afteraddition of methanolic hydrochloric acid, the1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-phenyl-imidazolidin-2-one-hydrochloride crystallises outand is purified by recrystallisation from isopropanol. Melting point:185°-187° C.

EXAMPLE 10

A solution of 5 g of 1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-phenyl-2-imino-imidazolidine-hydrochloride in 50 ml ofconc. hydrochloric acid and 50 ml of ethanol is refluxed for 8 hours in50 ml of ethanol. The solution is evaporated to dryness in vacuo and theresidue is recrystallised from isopropanol. The 1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-phenyl-imidazolidin-2-one-hydrochloride melts at 185°-187° C.

EXAMPLE 11

19.6 g of 1-(4-piperidyl)-3-phenyl-imidazolidin-2-one and 18 g of1-(2-methoxyphenyloxy)-2,3-epoxy-propane are refluxed for 6 hours in 500ml of isopropanol. The clear solution is then acidified with methanolichydrochloric acid and evaporated to dryness. The residue isrecrystallised twice from isopropanol. The1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-phenyl-imidazolidin-2-one-hydrochloride melts at 185°-187° C.

The 1-(4-piperidyl)-3-phenyl-imidazolidin-2-one can be prepared asfollows:

120 g of phenylethylenediamine and 164.4 g of 1-benzyl-4-piperidone aredissolved in 600 ml of methanol and, after addition of a 5% platinum oncharcoal catalyst, hydrogenated at 20°-30° C and under normal pressurefor 11 hours until cessation. The catalyst is removed by suctionfiltration and the filtrate is evaporated to dryness. The volatileconstituent is expelled with toluene and the residue is dissolved in 300ml of ethanol and crystallised with 150 ml of water. The crystals arecollected with suction at 5°-10° C and washed with two 50 ml portions ofethyl alcohol-water (2:1) and dried. The synthesised1-benzyl-4-(anilino-ethylamino)-piperidine has a melting point of88°-91° C.

200 g of 1-benzyl-4-(2-anilino-ethylamino)-piperidine and 2000 ml oftoluene and 1940 ml of potassium hydroxide solution are charged into areaction vessel. The temperature is kept between 5° and 10° C with amixture of ice and methanol while 300 g of phosgene are introduced inthe course of 3 hours. Thereafter the reaction mixture is stirred for 2hours at room temperature. During the dropwise addition of 860 ml ofpotassium hydroxide, the temperature is kept below 25° C with anice-bath. The batch is then stirred for 14 hours. The precipitatedcrystals are collected with suction and dried. The two-phase filtrate isseparated in a separating funnel. The toluene phase is dried over 200 gof sodium sulphate, filtered and concentrated. The residue isrecrystallied from 400 ml of ethanol to give the1-(1-benzyl-4-piperidyl)-3-phenyl-imidazolidin- 2-one with a meltingpoint of 173°-174° C.

A mixture of 151 g of 1-(1-benzyl-4-piperidyl)-3-phenyl-imidazolidin-2-one, 1100 ml of methanol, 45 g of hydrochloric acid (chemically pure),500 ml of water and 15 g of palladium on charcoal catalyst ishydrogenated at 30°-35° C and under normal pressure until thetheoretical amount of hydrogen has been taken up. The catalyst isremoved by suction filtration and the filtrate is concentrated by rotaryevaporation. The residue is dissolved in 200 ml of water, water,solution is made alkaline with 100 ml of conc. ammonia (minimum pH 12)and extracted with five 300 ml portions of methylene chloride. Thepurified extracts are dried over Na₂ SO₄ and concentrated. The residualcolourless oil crystallises after some time. The 103 g of crystallinesubstance are dissolved in 600 ml of ethyl acetate under reflux,insoluble material is filtered off hot and the filtrate is concentratedby rotary evaporation to a volume of approx. 500 ml and allowed tocrystaise. White crystalls of1-(4-piperidyl)-2-phenyl-imidazolidin-2-one with a melting point of123°-125° C are obtained.

EXAMPLE 12

Tablets containing 20 mg of1{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-phenyl-imidazolidin-2-one-hydrochloride can be preparedfor example as follows:

    ______________________________________                                        Composition (for 10,000 tablets)                                              ______________________________________                                        1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-                             piperidyl}-3-phenyl-imidazolidin-2-one-hydrochloride                                                        200 g                                           lactose                       300 g                                           corn starch                   300 g                                           colloidal silicic acid        50 g                                            talc                          50 g                                            magnesium stearate            10 g                                            water                         q.s.                                            ______________________________________                                    

The 1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-phenyl-imidazolidin-2-one-hydrochloride is mixed with a portion ofthe corn starch, with the lactose and the colloidal silicic acid and themixture is passed through a sieve. A further portion of the corn starchis pasted on a water bath with 5 times the amount of water and thepowder mixture is kneaded with the resultant paste until a slightlyplastic mass is obtained. This mass is forced through a sieve, dried,and the dry granules are passed through a sieve. The remainder of thecorn starch, the talc and the magnesium stearate are then admixed andthe resultant mixture is pressed into tablets each weighing 0.1 g withbreaking notch.

We claim:
 1. Oxygenated N-aryldiazacyclic compounds of the formula##STR13## wherein R₁, represents a phenyl or naphthyl group which isunsubstituted or substituted by a member selected from the groupconsisting of lower alkyl, lower alkoxy-lower alkyl, loweralkoxycarbonylamino-lower alkyl, lower alkenyl, hydroxyl, lower alkoxy,phenol-lower alkoxy, lower alkoxy-lower alkoxy, lower alkylthio-loweralkoxy, lower alkanoyl-lower alkoxy, lower alkenyloxy, lower alkinyloxy,lower alkylthio, halogen, lower alkanoyl, lower alkoxy-carbonyl,carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, cyano,nitro, lower alkanoylamino, lower alkoxycarbonylamino, 3-loweralkylureido and/or 3-cycloalkyl-ureido, ore represents pyridyl which isunsubstituted or substituted by a member selected from the groupconsisting of lower alkyl, lower alkoxy, lower alkylthio and/or halogen,R₂ represents a phenyl or naphthyl group which is unsubstituted orsubstituted by a member selected from the group consisting of loweralkyl, halogen-lower alkyl, lower alkoxy, halogen, lower alkanoyl, loweralkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-loweralkylcarbamoyl, nitro and/or di-lower alkylamino, or represents pyridylwhich is unsubstituted or substituted by a member selected from thegroup consisting of lower alkyl, lower alkoxy and/or halogen, and alkrepresents ethylene, or a pharmaceutically acceptable acid addition saltthereof.
 2. Oxygenated N-aryldiazacyclic compounds of the formula Iaccording to claim 1, wherein R₁ represents a phenyl group which isunsubstituted or substituted by a member selected from group consistingof lower alkyl, lower alkenyl, hydroxyl, lower alkoxy, phenyl-loweralkoxy, lower alkanoyl-lower alkoxy, lower alkenyloxy, lower alkinyloxy,halogen and/or cyano, R₂ represents a phenyl or naphthyl group which isunsubstituted or substituted by a member selected from the groupconsisting of lower alkyl, trifluoromethyl, lower alkyloxy, halogen,lower alkanoyl, lower alkoxycarbonyl, carbamoyl, nitro and/orN,N-di-lower alkylamino, or represents a pyridyl group which isunsubstituted or substituted by a member selected from the groupconsisting of lower alkyl, lower alkoxy and/or halogen, and alkrepresents ethylene.
 3. Oxygenated N-aryldiazacyclic compounds of theformula I according to claim 1, wherein R₁ represents a phenyl groupwhich is substituted in the ortho-position by a member selected from thegroup consisting of lower alkyl, lower alkenyl, lower alkoxy, hydroxyl,hydroxy, benzyloxy, lower alkenyloxy, lower alkinyloxy, loweralkanoyl-lower alkoxy, halogen or cyano, R₂ represents a phenyl groupwhich is unsubsituted or substituted by a member selected from the groupconsisting of lower alkyl, trifluoromethyl, lower alkoxy, halogen, loweralkanoyl, lower alkoxycarbonyl, carbamoyl, nitro and/or di-loweralkylamino, or represents a pyridyl group which is unsubstituted orsubstituted by lower alkyl or lower alkoxy, and alk represents theethylene group.
 4. Oxygenated N-aryldiazacyclic compounds of the formulaI according to claim 1, wherein R₁ represents phenyl which issubstituted in the ortho-position by a member selected from the groupconsisting of lower alkyl, lower alkenyl, lower alkenyloxy, halogen,cyano or lower alkoxy, R₂ represents phenyl which is unsubstituted orsubstituted by lower alkyl, lower alkoxy or halogen, or representspyridyl and alk represents the ethylene group.
 5. A compound accordingto claim 1, which is1-{1-[2-Hydroxy-3-(2-methoxyphenyloxy)-pyropyl]-4-piperidy}-3-phenyl-imidazolidin-2-one.6. A compound according to claim 1, which is1-{1-[2-Hydroxy-3-(2-methoxyphenoxy)propyl]-4-piperidyl}-3-(4-methoxy-phenyl)-imidazolidin-2-one.7. A pharmaceutical composition useful in the treatment of hypertensionin a warmblooded animal comprising a therapeutically effective amount ofa compound according to claim 1 or of a pharmaceutically acceptable acidaddition salt thereof together with a pharmaceutical carrier.
 8. Apharmaceutical composition according to claim 7 which contains1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-phenyl-imidazolidin-2-one,or a pharmaceutically acceptable acid addition salt thereof.
 9. A methodof treating hypertension in a warm blooded animal which comprisesadministering to said animal a therapeutically effective amount of acompound according to claim 1, or a pharmacologically acceptable acidaddition salt.
 10. A method according to claim 9 which comprisesadministering a therapeutically effective amount of1-{1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-piperidyl}-3-phenyl-imidazolidin-2-one.